Methylnaltrexone nasal formulations, methods of making, and use thereof

ABSTRACT

Methylnaltrexone nasal formulations are discloses which provide improved bioavailability over oral dosage forms and improved patient compliance over injectable dosage forms. Also disclosed are methods of making the nasal formulations and methods of using, specifically to treat the side effects of opioid drug use, such as constipation, and other indications.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 13/971,870, filed Aug. 21, 2013, which claims thebenefit of U.S. Provisional Application Ser. No. 61/691,943 filed Aug.22, 2012, each of which is incorporated herein by reference in itsentirety.

BACKGROUND

Clinicians often use opioids to treat patients with moderate-to-severepain. Opioids, however, often result in side effects such as inducing oraggravating constipation as these drugs react at receptors outside thetargeted central nervous system. Severe opioid-induced constipation mayresult in patient refusal to be treated with opioid therapy.

Opioid-induced constipation is predominantly mediated bygastrointestinal μ-opioid receptors as well as kappa receptors.Selective blockade of these peripheral receptors might relieveconstipation without compromising centrally mediated effects of opioidanalgesia or precipitating withdrawal.

Methylnaltrexone is a quaternary derivative of naltrexone and aperipherally-acting μ-opioid antagonist. It has restricted ability tocross the blood—brain barrier in humans because of its polarity and lowlipid solubility. In healthy volunteers, intravenous or oraladministration of methylnaltrexone was found to reverse opioid-inducedreduction in bowel motility without affecting analgesia.

Methylnaltrexone and methylnaltrexone salts have poor absorption in thegastrointestinal system thereby rending orally administeredmethylnaltrexone with limited bioavailability.

Methylnaltrexone bromide is currently available as a subcutaneousinjection to treat the side effects of opioid drug use, such asopioid-induced constipation. The dosage amount for the subcutaneousroute is approximately 0.15 mg/kg while the oral route is approximately3.2 mg/kg to 6.4 mg/kg, which is about twenty times higher than thesubcutaneous route.

Thus, there remains a need in the art for formulations and methods ofadministering methylnaltrexone that will require lower doses compared toorally administered formulations and better patient compliance comparedto subcutaneous and injectable formulations.

SUMMARY

In one embodiment, a liquid mucoadhesive intranasal dosage formulationcomprises methylnaltrexone, a pharmaceutically acceptable salt ofmethylnaltrexone, a pharmaceutically acceptable ester ofmethylnaltrexone, or a combination thereof; a mucoadhesive agent; and aliquid carrier; wherein the formulation does not substantially drip fromthe intranasal cavity after administration of a single dose

In one embodiment, a method of administering methylnaltrexone to apatient in need thereof comprises intranasally administering to apatient a liquid mucoadhesive intranasal dosage formulation comprisingmethylnaltrexone, a pharmaceutically acceptable salt ofmethylnaltrexone, a pharmaceutically acceptable ester ofmethylnaltrexone, or a combination thereof; a mucoadhesive; and a liquidcarrier, wherein the formulation does not substantially drip from theintranasal cavity after administration of a single dose.

DETAILED DESCRIPTION

Disclosed herein are viscous or shear thinning liquid mucoadhesiveintranasal dosage formulations of methylnaltrexone, a pharmaceuticallyacceptable salt of methylnaltrexone, a pharmaceutically acceptable esterof methylnaltrexone, or a combination thereof which do not substantiallydrip or which do not drip out of the patient's nasal cavity after asingle dose has been administered. There are many advantages to theseformulations including ease of administration for example by spraying,improved bioavailability compared to oral methylnaltrexone formulations,and smaller doses compared to oral formulations resulting in fewer sideeffects. Additionally, the nasal formulations will have better patientcompliance compared to injectable formulations.

Administration of methylnaltrexone to the nasal mucosa allows for fasteronset and higher bioavailability compared to oral administration.

Administration of methylnaltrexone intranasally requires less activeagent compared to oral formulations, and thus there is reduced toxicity.

Since intranasally administered methylnaltrexone is not absorbed throughthe gut, the first pass effect is avoided to result in higherbioavailability.

In an embodiment, a small volume (e.g. <200 microliters) of mucoadhesivenasal formulation will adhere to the nasal mucosa and will not cause anypost nasal drip into the throat.

The liquid nasal formulation is formulated in a way that allows for theadherence to the nasal cavity of the patient without substantial loss offormulation to the back of the patient's throat. Preparation of aformulation with a mucoadhesive agent and having an adequate viscosityresults in a formulation that does not leak down the back of the nasalcavity into the patient's throat and eventually to the gastrointestinaltract where the active agent is less bioavailable. Furthermore, to avoidloss of the formulation out of the nasal cavity and to promoteabsorption of the active, the formulation is administered in smallamounts (e.g. about 50 to about 200 microliters per dose). Additionally,a nasal inhaler/spray system can be used to avoid post-nasal runoff,aftertaste, or drip. Since, the bioavailability of methylnaltrexone isless through oral route compared to the nasal route, any drug that dripsinto the throat will enter the gastrointestinal tract resulting indecreased bioavailability and/or high variations in bioavailability.Thus, the nasal formulations comprise a mucoadhesive agent to increasethe viscosity of the formulations and to provide longer residence timeson the nasal mucosa partially due to physical forces that resist nasalcilia clearance. The resulting formulation does not drip or does notsubstantially drip from the patient's intranasal cavity after a singledose of the formulation has been administered.

Disclosed herein are liquid mucoadhesive intranasal dosage formulationscomprising methylnaltrexone, a pharmaceutically acceptable salt ofmethylnaltrexone, a pharmaceutically acceptable ester ofmethylnaltrexone, or a combination thereof; a mucoadhesive agent; and aliquid carrier, wherein the mucoadhesive is viscous and thixotropic innature, and wherein the formulation does not substantially drip or doesnot drip from the intranasal cavity after administration.

As used herein, “nasal administration” means the same as “intranasaladministration” wherein the formulation is administered to the interiorof the nasal cavity.

As used herein, “does not substantially drip from the intranasal cavityafter administration” means there is less than 10% of the intranasallyadministered dose of formulation that migrates out of the external naresor from the nasopharynx to the laryngopharynx and pharynx.

The formulation comprises methylnaltrexone, a pharmaceuticallyacceptable salt of methylnaltrexone, a pharmaceutically acceptable esterof methylnaltrexone, or a combination thereof. An exemplarymethylnaltrexone salt is methylnaltrexone bromide.

“Pharmaceutically acceptable salt” includes derivatives of a compound,wherein the compound is modified by making acid or base addition saltsthereof, and with regard to an active agent further refers topharmaceutically acceptable solvates, including hydrates, crystallineforms, non-crystalline forms, and polymorphs, of such salts. Examples ofpharmaceutically acceptable salts include, but are not limited to,mineral or organic acid addition salts of basic residues such as amines;alkali or organic addition salts of acidic residues; and the like, or acombination thereof. For example, acid salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; other acceptable inorganic saltsinclude metal salts such as sodium salt, potassium salt, cesium salt,and the like; and alkaline earth metal salts, such as calcium salt,magnesium salt, and the like, or a combination thereof. Pharmaceuticallyacceptable organic salts includes salts prepared from organic acids suchas acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic,2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC—(CH₂)_(n)—COOH where n is 0-4, andthe like; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, and the like;and amino acid salts such as arginate, asparginate, glutamate, and thelike; or a combination thereof.

The methylnaltrexone, a pharmaceutically acceptable salt ofmethylnaltrexone, a pharmaceutically acceptable ester ofmethylnaltrexone, or a combination thereof can be present in the liquidmucoadhesive intranasal dosage formulation in an amount about 4 to about200 mg of methylnaltrexone per dose, specifically about 5 to about 150mg per dose, and yet more specifically 8 to about 100 mg per dose.

The liquid mucoadhesive intranasal dosage formulation further comprisesa mucoadhesive agent. The mucoadhesive agent imparts a mucoadhesiveproperty to the formulation so that the formulation remains in the nasalcavity and does not drip out of the nose either from the external nares(nostrils) or the back of the throat. Nasal Mucociliary Clearance is oneof the limiting factors for nasal drug delivery, because it reduces thetime allowed for drug absorption. Thus, improving nasal drug absorptioncan be achieved by prolonging the contact time between the drug and thenasal mucosa. Mucoadhesion implies the attachment of the drugformulation to the nasal mucus membranes, involving an interactionbetween mucin and a mucoadhesive agent, a synthetic or natural polymer.The sequential events that occur during mucoadhesion include a firststep where the mucoadhesive agent absorbs water from the nasal mucosaand swells. The mucoadhesive agent then intimately penetrates into thenasal mucosa and, hence, localizes the formulation in nasal cavity,enhancing the drug concentration gradient across the epithelium.

Exemplary mucoadhesive agents include an alginate (e.g. sodiumalginate), a cellulose and cellulose derivatives (e.g.carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,microcrystalline cellulose, a combination thereof, and the like),chitosan, gelling proteins (e.g. gelatin), hydroxyethyl methacrylate, amodified starch (e.g. thermally modified starch, and the like), naturalgums and polysaccharides (e.g. Acacia, gum Arabic, Guar gum, gum Karaya,pectin, tragacanth, a combination thereof, and the like), a polyacrylicacid (e.g. CARBOPOL® 934P from Lubrizol CAS no. 9003-01-4), apoly(acrylic acid/divinyl benzene), a poly(lactic acid), a polycarbophil(i.e. polyacrylic acid cross-linked with divinyl glycol), polyvinylpyrrolidone, psyllium, a resin (e.g. Amberlite-200 a cation exchangeresin based on sulfonic acid exchange groups on a polystyrenic matrix,and the like), or a combination thereof. Specific mucoadhesive agentsinclude microcrystalline cellulose, carboxymethylcellulose sodium,polyvinyl pyrrolidone, or a combination thereof.

The mucoadhesive agent can be present in the formulation in an amount ofabout 1.0 to about 25% w/v, specifically about 2.0 to about 10, and morespecifically about 3.0 to about 5% w/v.

The formulation further comprises a pharmaceutically acceptable liquidcarrier to dissolve or suspend the ingredients. Exemplarypharmaceutically acceptable liquid carriers include purified water; andpharmaceutically acceptable organic liquid carriers, for exampleglycerin; propylene glycol; a lower molecular weight polyethylene glycol(e.g., polyethylene glycol 200, polyethylene glycol 300, polyethyleneglycol 400, polyethylene glycol 540, polyethylene glycol 600, and thelike); ethanol; propylene carbonate; or a combination thereof.

The formulation can optionally further comprise an intranasalformulation excipient such as a buffering agent, a flavoring agent, asweetening agent, a tonicity agent, an antimicrobial preservative, anantimicrobial preservative synergist, a surfactant, an emulsifier, asolubilizer, an absorption enhancer, or a combination thereof. In someinstances, a single compound or material will meet two or more of theforegoing general classifications. For example, a compound may functionas both an emulsifier and a surfactant.

The liquid mucoadhesive intranasal dosage formulation can furtherinclude an antimicrobial preservative to prevent the unwanted growth ofbacteria, molds, fungi, or yeast. Examples of suitable antimicrobialpreservatives include benzyl alcohol, benzalkonium chloride, benzoicacid alkali metal salts (e.g., sodium benzoate), sorbic acid alkalimetal salts (e.g., potassium sorbate), sodium erythorbate, sodiumnitrite, calcium sorbate, butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT), parabens (e.g., lower alkyl esters ofpara-hydroxybenzoic acid), alkali metal salts of parabens includingsodium and potassium salts of methyl-, ethyl-, propyl-, or butylparaben,or a combination thereof. Specific antimicrobial preservatives includebenzyl alcohol, benzalkonium chloride, or a combination thereof.

The antimicrobial preservative can be present in the liquid mucoadhesiveintranasal dosage formulation in an amount of about 0.001 to about 1.0%w/v, specifically about 0.01 to about 0.55% w/v, and yet morespecifically about 0.1 to about 0.3% w/v.

The liquid mucoadhesive intranasal dosage formulation can furtheroptionally include an antimicrobial preservative synergist such asethylenediaminetetraacetic acid (EDTA) or pharmaceutically acceptablesalts there of (e.g. calcium disodium EDTA). The antimicrobialpreservative synergist can be present in the formulation in an amount ofabout 0.001 to about 0.1% w/v, specifically about 0.01 to about 0.05%w/v, and more specifically about 0.02 to about 0.04% w/v.

The liquid mucoadhesive intranasal dosage formulation can be isotonic orisotonic and buffered. The liquid mucoadhesive intranasal dosageformulation may optionally comprise a tonicity agent such as dextrose,glycerin, mannitol, potassium chloride, sodium chloride, or acombination thereof. The amount of tonicity agent can be determined byone having ordinary skill in the art without undue experimentation.

The liquid mucoadhesive intranasal dosage formulation can comprise abuffering agent. Exemplary buffering agents include citrates, acetates,phosphates (e.g. citric acid, sodium citrate, sodium acetate, dibasicsodium phosphate, monobasic sodium phosphate, or a combination thereof).

In an embodiment, the liquid carrier comprising non-active ingredientsfor use to prepare the mucoadhesive intranasal dosage formulation canhave a pH of about 5.5 to about 7.5, specifically about 6.0 to about7.0.

A sweetening agent can optionally be included in the formulation to makethe composition palatable to the patient and to improve patientcompliance. Exemplary sweetening agents include sugar alcohols (orpolyols), such as glycerol, sorbitol, xylitol, mannitol, galactitol,maltitol, hydrogenated isomaltulose (isomalt), lactitol, erythritol,glucitol, ribitol, or a combination thereof; sugar sweeteners generallyinclude saccharides, such as mono-saccharides, di-saccharides andpoly-saccharides such as sucrose (saccharose, sugar), dextrose, maltose,dextrin, maltodextrin, xylose, ribose, glucose (including liquidglucose), mannose, galactose, fructose (levulose), lactose, invertsugar, fructo oligo saccharide syrups, trehalose, tagatose, fucose,gulose, raffinose, ribulose, rufinose, stachyose, xylulose, adonose,amylase, arabinose, deoxyribose, corn syrup solids, such as highfructose corn syrup, or a combination thereof; artificial sweetenerssuch as soluble saccharin salts, i.e., sodium or calcium saccharinsalts, the potassium salt of3,4-dihydro-6-methyl-1,2,3-oxathiazine-4-one-2,2-dioxide (Acesulfame-K),the free acid form of saccharin, L-aspartic acid derived sweeteners,such as L-aspartyl-L-phenylalanine methyl ester (Aspartame),L-alphaaspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamidehydrate (Alitame), N-[N-(3,3-dimethylbutyl)-L-aspartyl]-L-phenylalanine1-methyl ester (Neotame), methyl esters of L-aspartyl-L-phenylglycerineand L-aspartyl-L-2,5-dihydrophenyl-glycine,L-aspartyl-2,5-dihydro-L-phenylalanine;L-aspartyl-L-(1-cyclohexen)-alanine, or a combination thereof;sucralose; maltol; or a combination thereof.

When used, the sweetening agent can be present in the liquidmucoadhesive intranasal dosage formulation in an amount of about 0.1 toabout 10% w/v, specifically about 0.2 to about 5.0% w/v, and morespecifically about 0.5 to about 3.0 % w/v. The amount of sweeteningagent can be determined by one of ordinary skill in the art withoutundue experimentation.

The liquid mucoadhesive intranasal dosage formulation may optionallyfurther comprise a flavoring agent. Flavoring agents include thoseflavors known to one of ordinary skill in the art, such as naturalflavors and artificial flavors. Suitable amounts of flavoring agent canbe selected by one of ordinary skill in the art without undueexperimentation. In one embodiment, the flavoring agent can be presentin the liquid composition from about 0.1 to about 5.0% w/v, specificallyabout 0.15 to about 3% w/v, and more specifically about 1.0 to about2.0% w/v.

The liquid mucoadhesive intranasal dosage formulations may furthercomprise a surfactant (ionic, non-ionic, or a combination thereof), anemulsifier, a solubilizer, an absorption enhancer, or a combinationthereof. In some instances, a single material will meet two or more ofthe foregoing general classifications.

Exemplary emulsifier/solubilizer include polyoxyethylene castor oilderivatives including polyoxyl 5 castor oil, polyoxyl 9 castor oil,polyoxyl 15 castor oil, polyoxyl 35 castor oil (CREMOPHOR EL from BASF),polyoxyl 40 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60hydrogenated castor oil, and the like, or a combination thereof. Theseemulsifiers/solubilizers are suitable to prepare the formulation as anemulsion or by complexation.

Exemplary non-anionic surfactants include glyceryl monooleate, apolyoxyethylene alkyl ether, a polyoxyethylene castor oil derivative, apolyoxyethylene sorbitan fatty acid ester, a polyoxyethylene stearate, apolysorbate 80 (TWEEN 80), a sorbitan ester, and the like, or acombination thereof. These surfactants are suitable to prepare theformulation as an emulsion or by complexation.

Exemplary anionic surfactants include docusate salts such as sodium,potassium, or calcium docusate; sodium lauryl sulfate, self-emulsifyingglyceryl monooleate, and the like, or a combination thereof. Thesesurfactants are suitable to prepare the formulation by complexation.

Absorption enhancers are compounds use to enhance the absorption of theactive agent across the nasal membrane either by solubilizing orstabilizing the active agent, altering the property of the nasalmembrane, or a combination thereof. Exemplary absorption enhancersinclude a surfactant (e.g., polidocanol), a bile salt, a fatty acid(e.g., taurodihydrofusidate), chitosan, a cyclodextrin, poly-L-arginine,aminated gelatin, or a combination thereof.

The total amount of surfactant, emulsifier, solubilizer, an absorptionenhancer, or a combination thereof in the liquid mucoadhesive intranasaldosage formulation can be from about 0.1 to about 8.0% w/v, specificallyabout 0.15 to about 6% w/v, and more specifically about 1.0 to about5.0% w/v.

A pH adjusting agent may optionally be used to render the final liquidmucoadhesive intranasal dosage formulation to a targeted pH. Suitable pHadjusting agents include pharmaceutically acceptable acids, bases, andtheir salts. Exemplary pH adjusting agents include alkali metalhydroxides (e.g., sodium hydroxide and potassium hydroxide),hydrochloric acid, alkali metal carbonates (e.g., sodium carbonate andpotassium carbonate), carbonic acid, or a combination thereof. The pHadjusting agents can be used as solutions or suspensions in apharmaceutically acceptable solvent. Suitable pharmaceuticallyacceptable solvents for use with the pH adjusting agent can includepurified water, lower alkyl alcohols such as ethanol, a glycol, and thelike, or a combination thereof.

The amount of pH adjusting agent can be any amount to result in adesired pH of the final liquid mucoadhesive intranasal dosageformulation. Such amounts can be determined by one having ordinary skillin the art without undue experimentation.

The liquid mucoadhesive intranasal dosage formulation may optionallyfurther comprise an intranasal formulation excipient such as asolid-grade polyethylene glycol (i.e. those that have a molecular weightat or above 1000 such as PEG 1000, PEG 1450, PEG 3350, and the like).

The liquid mucoadhesive intranasal dosage formulation can beadministered as an aerosol or spray using a suitable device. Theformulations can be administered using a device such as a dropper,atomizer, or spray device. The device can be a squeeze spray device or ametered valve and pump device. An exemplary metered dose device includes3M™ Nasal MDI.

Also included herein are pharmaceutical kits comprising the liquidmucoadhesive intranasal dosage formulation and a device to intranasallydeliver the liquid mucoadhesive intranasal dosage formulation. The kitsmay further comprise one or more conventional pharmaceutical kitcomponents, such as, for example, one or more containers to aid infacilitating compliance with a particular dosage regimen; one or morecarriers; printed instructions, either as inserts or as labels,indicating quantities of the components to be administered, orguidelines for administration. Exemplary kits can be in the form ofprepackaged, single use devices, or devices comprising multiple doses.The formulations can be packaged in a dropper, atomizer, or spraydevice. The device can be a squeeze spray device or a metered valve andpump device. In one embodiment, the kit comprises the liquidmucoadhesive intranasal dosage formulation and a metered dose spraydevice which can consistently deliver about 50 to about 200 microlitersof the formulation per spray to prevent dripping of the formulation tothe throat and to promote absorption through the nasal mucosa.

Each dose can contain an amount of about 4 to about 200 mg ofmethylnaltrexone, a pharmaceutically acceptable salt ofmethylnaltrexone, a pharmaceutically acceptable ester ofmethylnaltrexone, or a combination thereof, specifically about 5 toabout 150 mg per dose, and yet more specifically 8 to about 100 mg perdose.

The liquid mucoadhesive intranasal dosage formulation can beadministered to a patient in need of treatment of opioid-induced sideeffects, including opioid induced constipation; or administered to apatient in need of treatment of irritable bowel syndrome (IBS).

The features and advantages are more fully shown by the followingexamples which are provided for purposes of illustration, and are not tobe construed as limiting the invention in any way.

EXAMPLES Example 1. Methylnaltrexone Nasal Solution

A methylnaltrexone bromide nasal solution is prepared using acellulose-based mucoadhesive. The formulation is provided in Table 1with amounts in percent weight/volume (% w/v).

TABLE 1 Lower Target Upper Ingredients % w/v MNTX-Br (MethylnaltrexoneBr) 0.05 0.1 2 Microcrystalline cellulose and 2.5 3 3.5Carboxymethylcellulose sodium (Avicel ® RC 591, FMC Corporation)Monobasic sodium phosphate 0.1 0.5525 1 Dibasic sodium phosphate 0.010.0975 0.3 Povidone K29-32 1 3 5 Polyethylene Glycol 1450 2 5 10Benzalkonium Chloride solution 17% 0.01 0.11449 0.5 Benzyl Alcohol 0.10.25 0.5 EDTA 0.01 0.03 0.05 Sucralose 0.1 0.2 0.5 Peppermint Flavor 0.10.15 1 Water, purified qs qs qs

The nasal solution formulation is prepared by placing approximately 50%of the batch quantity of purified water in a beaker. Avicel is added tothe water in the beaker and mixed to ensure wetting of all powder. In aseparate beaker, purified water in an amount of approximately 25% of thebatch quantity is added, followed by EDTA, sodium phosphate monobasic,sodium phosphate dibasic, and povidone. To this mixture polyethyleneglycol 1450 is added and mixed together. The Avicel solution is added tothe povidone solution via an in-line disperser. In a third beakercontaining a small quantity of purified water is added the benzalkoniumchloride solution, benzyl alcohol, peppermint, Sucralose andmethylnaltrexone bromide; the contents are mixed until dissolved. Themethylnaltrexone solution is added to the Avicel/povidone solution andmixed well to form a nasal solution. The nasal solution formulation isthen packaged in a metered dose spray bottle.

Example 2. Methylnaltrexone Nasal Emulsion

A methylnaltrexone bromide nasal emulsion formulation is prepared usinga cellulose-based mucoadhesive and a non-ionicsurfactant/emulsifier/solubilizer. The formulation is provided in Table2.

TABLE 2 Lower Target Upper Ingredients % w/v MNTX-Br (MethylnaltrexoneBr) 0.05 0.1 2 Polysorbate 80 (Tween 80) 0.05 0.1 1 Polyethoxylatedcastor oil (Cremophore EL, 0.05 0.1 1 BASF) Microcrystalline celluloseand 2.5 3 3.5 Carboxymethylcellulose sodium (Avicel ® RC 591, FMCCorporation) Monobasic sodium phosphate 0.1 0.5525 1 Dibasic sodiumphosphate 0.01 0.0975 0.3 Povidone K29-32 1 3 5 Polyethylene Glycol 14502 5 10 Benzalkonium Chloride solution 17% 0.01 0.11449 0.5 BenzylAlcohol 0.1 0.25 0.5 EDTA 0.01 0.03 0.05 Sucralose 0.1 0.2 0.5Peppermint Flavor 0.1 0.15 1 Water, purified qs qs qs

The nasal emulsion formulation is prepared by placing approximately 50%of the batch quantity of purified water in a beaker. Avicel is added tothe water in the beaker and mixed to ensure wetting of all powder. In aseparate beaker, purified water in an amount of approximately 25% of thebatch quantity is added, followed by Tween 80, Cremophore EL, EDTA,sodium phosphate monobasic, sodium phosphate dibasic, and povidone. Tothis mixture polyethylene glycol 1450 is added and mixed together. TheAvicel solution is added to the povidone solution via an in-linedisperser. In a third beaker containing a small quantity of purifiedwater is added the benzalkonium chloride solution, benzyl alcohol,peppermint, Sucralose and methylnaltrexone bromide; the contents aremixed until dissolved. The methylnaltrexone solution is added to theAvicel/povidone solution and mixed well to form a nasal emulsionformulation. The nasal emulsion formulation is then packaged in ametered dose spray bottle.

Example 3. Methylnaltrexone Nasal Formulation: Complexation

A methylnaltrexone bromide nasal formulation is prepared using acellulose-based mucoadhesive and complexation with an anionicsurfactant. The formulation is provided in Table 3.

TABLE 3 Lower Target Upper Ingredients % w/v MNTX-Br (MethylnaltrexoneBr) 0.05 0.1 2 Docusate Sodium 0.05 0.1 1 Polyethoxylated castor oil(Cremophore EL, 0.05 0.1 1 BASF) Microcrystalline cellulose and 2.5 33.5 Carboxymethylcellulose sodium (Avicel ® RC 591, FMC Corporation)Monobasic sodium phosphate 0.1 0.5525 1 Dibasic sodium phosphate 0.010.0975 0.3 Povidone K29-32 1 3 5 Polyethylene Glycol 1450 2 5 10Benzalkonium Chloride solution 17% 0.01 0.11449 0.5 Benzyl Alcohol 0.10.25 0.5 EDTA 0.01 0.03 0.05 Sucralose 0.1 0.2 0.5 Peppermint Flavor 0.10.15 1 Water, purified qs qs qs

The nasal emulsion formulation is prepared by placing approximately 50%of the batch quantity of purified water in a beaker. Avicel is added tothe water in the beaker and mixed to ensure wetting of all powder. In aseparate beaker, purified water in an amount of approximately 25% of thebatch quantity is added, followed by Docusate Sodium, Cremophore EL,EDTA, sodium phosphate monobasic, sodium phosphate dibasic, andpovidone. To this mixture polyethylene glycol 1450 is added and mixedtogether. The Avicel solution is added to the povidone solution via anin-line disperser. In a third beaker containing a small quantity ofpurified water is added the benzalkonium chloride solution, benzylalcohol, peppermint, Sucralose and methylnaltrexone bromide; thecontents are mixed until dissolved. The methylnaltrexone solution isadded to the Avicel/povidone solution and mixed well to form a nasalformulation. The nasal formulation is then packaged in a metered dosespray bottle.

The terms “comprising”, “having”, “including”, and “containing” are tobe construed as open-ended terms (i.e., meaning “including, but notlimited to”). The terms “a” and “an” do not denote a limitation ofquantity, but rather denote the presence of at least one of thereferenced item. The term “or” means “and/or”. The endpoints of allranges directed to the same component or property are inclusive andindependently combinable. The modifier “about” used in connection with aquantity is inclusive of the stated value and has the meaning dictatedby the context (e.g., includes the degree of error associated withmeasurement of the particular quantity). The term “or a combinationthereof” means a combination of one, two, or more of the listed items.Reference throughout the specification to “one embodiment”, “anotherembodiment”, “an embodiment”, and so forth, means that a particularelement (e.g., feature, structure, and/or characteristic) described inconnection with the embodiment is included in at least one embodimentdescribed herein, and may or may not be present in other embodiments. Inaddition, it is to be understood that the described elements may becombined in any suitable manner in the various embodiments.

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs.

While the invention has been described with reference to an exemplaryembodiment, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings of the invention without departing from theessential scope thereof. Therefore, it is intended that the inventionnot be limited to the particular embodiment disclosed as the best modecontemplated for carrying out this invention, but that the inventionwill include all embodiments falling within the scope of the appendedclaims.

1. A method of treating a patient in need of treatment of opioid-inducedside effects including opioid induced constipation, or a patient in needof treatment of irritable bowel syndrome (IBS), comprising: intranasallyadministering to a patient in need thereof a liquid mucoadhesiveintranasal dosage formulation comprising methylnaltrexone, apharmaceutically acceptable salt of methylnaltrexone, a pharmaceuticallyacceptable ester of methylnaltrexone, or a combination thereof; amucoadhesive; and a liquid carrier, wherein the formulation does notsubstantially drip from the intranasal cavity after administration of asingle dose; and the methylnaltrexone, a pharmaceutically acceptablesalt of methylnaltrexone, a pharmaceutically acceptable ester ofmethylnaltrexone, or a combination thereof is dissolved in the liquidcarrier.
 2. The method of claim 1, wherein the liquid mucoadhesiveintranasal dosage formulation comprises about 4 to about 200 mg ofmethylnaltrexone, a pharmaceutically acceptable salt ofmethylnaltrexone, a pharmaceutically acceptable ester ofmethylnaltrexone, or a combination thereof per dose.
 3. The method ofclaim 1, wherein the liquid mucoadhesive intranasal dosage formulationcomprises about 5 to about 150 mg of methylnaltrexone, apharmaceutically acceptable salt of methylnaltrexone, a pharmaceuticallyacceptable ester of methylnaltrexone, or a combination thereof per dose.4. The method of claim 1, wherein the liquid mucoadhesive intranasaldosage formulation comprises about 8 to about 100 mg ofmethylnaltrexone, a pharmaceutically acceptable salt ofmethylnaltrexone, a pharmaceutically acceptable ester ofmethylnaltrexone, or a combination thereof per dose.
 5. The method ofclaim 1, wherein the liquid mucoadhesive intranasal dosage formulationcomprises methylnaltrexone bromide.
 6. The method of claim 1, whereinthe mucoadhesive is an alginate, a cellulose or cellulose derivative,chitosan, a gelling protein, a hydroxyethyl methacrylate, a modifiedstarch, a natural gum, a polysaccharide, a polyacrylic acid, apoly(acrylic acid/divinyl benzene), a poly(lactic acid), apolycarbophil, polyvinyl pyrrolidone, psyllium, a resin, or acombination thereof.
 7. The method of claim 1, wherein the mucoadhesiveis microcrystalline cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, or a combination thereof.
 8. The method of claim 1, whereinthe mucoadhesive agent is present in an amount of about 1.0 to about 25%w/v.
 9. The method of claim 1, wherein the liquid carrier is purifiedwater, a pharmaceutically acceptable organic liquid carrier, or acombination thereof.
 10. The method of claim 1, wherein the liquidmucoadhesive intranasal dosage formulation further comprises anintranasal formulation excipient, a buffering agent, a flavoring agent,a sweetening agent, a tonicity agent, an antimicrobial preservative, anantimicrobial preservative synergist, a surfactant, an emulsifier, asolubilizer, an absorption enhancer, or a combination thereof.
 11. Themethod of claim 10, wherein the buffering agent is a sodium phosphate.12. The method of claim 10, wherein the antimicrobial preservative isbenzalkonium chloride, benzyl alcohol, sodium benzoate or a combinationthereof; and wherein the antimicrobial preservative synergist isethylenediaminetetraacetic acid or a pharmaceutically acceptable saltthereof.
 13. The method of claim 10, wherein the sweetening agent is anartificial sweetener.
 14. The method of claim 10, wherein the surfactantis a non-ionic surfactant.
 15. The method of claim 10, wherein thesurfactant, emulsifier, solubilizer, an absorption enhancer, or acombination thereof is a polyoxyethylene castor oil derivative, aglyceryl monooleate, a polyoxyethylene alkyl ether, a polyoxyethylenesorbitan fatty acid ester, a polyoxyethylene stearate, a polysorbate 80,a sorbitan ester, a docusate salt, sodium lauryl sulfate, aself-emulsifying glyceryl monooleate, or a combination thereof
 16. Themethod of claim 1, wherein the liquid mucoadhesive intranasal dosageformulation is in the form of a solution, emulsion, or complexationformulation.
 17. The method of claim 1, wherein the liquid mucoadhesiveintranasal dosage formulation can be administered as an aerosol orspray.
 18. The method of claiml, wherein the liquid mucoadhesiveintranasal dosage formulation is administered in an amount of about 50to about 200 microliters in the form of a spray.
 19. The method of claim1, wherein the liquid mucoadhesive intranasal dosage formulationcomprises about 0.05 to about 2% w/v methylnaltrexone bromide; about 1.0to about 25% w/v of a mucoadhesive agent, wherein the mucoadhesive ismicrocrystalline cellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, or a combination thereof; and a liquid carrier comprisingpurified water; wherein the formulation does not substantially drip fromthe intranasal cavity after administration of a single dose; and themethylnaltrexone bromide is dissolved in the liquid carrier.
 20. Themethod of claim 19, wherein the liquid mucoadhesive intranasal dosageformulation is administered in an amount of about 50 to about 200microliters in the form of a spray.